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J. Biol. Chem., Vol. 277, Issue 42, 39926-39936, October 18, 2002
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,
From the Institute of Cancer Research and Molecular Biology,
Norwegian University of Science and Technology,
N-7489 Trondheim, Norway
hUNG2 and hSMUG1 are the only known glycosylases
that may remove uracil from both double- and single-stranded DNA in
nuclear chromatin, but their relative contribution to base excision
repair remains elusive. The present study demonstrates that both
enzymes are strongly stimulated by physiological concentrations of
Mg2+, at which the activity of hUNG2 is
2-3 orders of magnitude higher than of hSMUG1. Moreover,
Mg2+ increases the preference of hUNG2 toward uracil in
ssDNA nearly 40-fold. APE1 has a strong stimulatory effect on hSMUG1
against dsU, apparently because of enhanced dissociation of hSMUG1 from AP sites in dsDNA. hSMUG1 also has a broader substrate specificity than
hUNG2, including 5-hydroxymethyluracil and
3,N4-ethenocytosine. hUNG2 is excluded from,
whereas hSMUG1 accumulates in, nucleoli in living cells. In
contrast, only hUNG2 accumulates in replication foci in the S-phase.
hUNG2 in nuclear extracts initiates base excision repair of plasmids
containing either U:A and U:G in vitro. Moreover, an
additional but delayed repair of the U:G plasmid is observed that is
not inhibited by neutralizing antibodies against hUNG2 or hSMUG1. We
propose a model in which hUNG2 is responsible for both prereplicative
removal of deaminated cytosine and postreplicative removal of
misincorporated uracil at the replication fork. We also provide
evidence that hUNG2 is the major enzyme for removal of deaminated
cytosine outside of replication foci, with hSMUG1 acting as a
broad specificity backup.
Present address: Cancer Research UK London Research Inst., Clare
Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, United Kingdom.
§
To whom correspondence should be addressed. Tel.:
47-73598693; Fax: 47-73598801; E-mail:
geir.slupphaug@medisin.ntnu.no.
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